The alkaloids obtainable from Vinca rosea represent one of the most productive areas of chemistry for drugs adversely affecting the growth of experimental malignancies in mammals. Initially, only some of the alkaloids, obtainable from the leaves of the plant by extraction and purifiable by chromatography, were found to be active. These active antineoplastic alkaloids obtained directly from the leaves of the vinca plant included VLB (Vinblastine, vincaleucoblastine), vincristine (leurocristine), leurosine (vinleurosine), leurosidine (vinrosidine), leuroformine (formylleurosine) and deoxy VLB "A" and "B" (4'-deoxy VLB and 4'-deoxyleurosidine). All are dimeric indole-dihydroindoles. Other less abundant antineoplastic alkaloids have also been found.
Chemical modification of the Vinca alkaloids started slowly for several reasons. In the first place, the molecular structures involved are extremely complex, and chemists were slow to find reactions which modified one specific functional group of the molecule without affecting other groups. Secondly, dimeric alkaloids lacking desirable chemotherapeutic properties had been recovered or produced from Vinca rosea extracts, and a determination of their structures had led to the conclusion that these inactive compounds were closely related structurally to, and even isomeric with, one or more of the active alkaloids. Thus, it appeared that small chemical changes in the known alkaloids could have a profound effect on antineoplastic activity.
Because of these restrictions, modification of the indole-dihydroindole alkaloids obtained from Vinca rosea has centered around three areas of the molecule C-3, C-4' and C-4. In the first place, one of the more recent, and more successful, modifications of the basic indole-dihydroindole structure has been the preparation of C-3 carboxamide and carboxhydrazide derivatives, most of which have turned out to be active anti-tumor agents. [See Cullinan et al., U.S. Pat. No. 4,203,898, Conrad et al., U.S. Pat. No. 4,191,688, Cullinan and Gerzon, U.S. Pat. No. 4,166,810, Conrad et al. J. Med. Chem., 22, 391 (1979), and Barnett et al. ibid, 21 88 (1978)]. One of the amides, 4-desacetyl VLB 3-carboxamide (VDS, vindesine), is currently being marketed in several European countries as an oncolytic agent. Vindesine is effective in treating some vincristine-resistant leukemias in addition to many common neoplasms including germ-cell tumors. Amides of leurosine and leuroformine are disclosed in U.S. Pat. No. 4,191,688.
In another type of modification, reaction of the 3-hydroxy and 3-ester functions of an indole-dihydroindole vinca alkaloid with an isocyanate has produced the corresponding oxazolidinedione derivatives, one of which, the N-chloroethyl derivative--vinzolidine--is currently undergoing a clinical trial in humans. These oxazolidinedione derivatives are disclosed in Miller and Gutowski, U.S. Pat. No. RE 30,560, reissued Mar. 31, 1981. Trouet et al., U.S. Pat. No. 4,388,305 disclose anticancer VLB C-3 peptides in which the peptide group contains 1-6 amino acid residues with a terminal free acid or ester group. These amides formed from one amino acid residue are also disclosed in column 15, lines 1-16, of Cullinan et al. (loc. cit.). Trouet et al also used the hydrazide-azide synthetic procedure of Cullinan et al.
In addition to the VLB, VCR etc. hydrazides from Cullinan et al, (loc cit.) and leurosine hydrazide disclosed in Neuss (et al) Tetrahedron Letters 783 (1968) (This article, in Table I, page 785, refers to compound XI as VLB hydrazide, but according to the footnote, the compound is actually an 18'-descarbomethoxy derivative-see also line 2 for the correct name for XI), 4-desacetyl VLB hydrazide derivatives are disclosed in Cullinan and Gerzon, U.S. Pat. No. 4,166,810. The named derivatives include mono C.sub.1-3 alkyl, .beta.-hydroxyethyl, ethyl, .beta.-acetoxyethyl, C.sub.2-4 alkanoyl, dichloroacetyl, benzoyl, C.sub.1-3 alkylcarbazyl, dimethyl and C.sub.1-3 alkylidine (.dbd.CRR' where R and R.sup.1 are H or methyl or one is ethyl).
Imide derivatives of vinca hydrazides are not known.